In intractable nervous diseases such as cerebral apoplexy and neurodegenerative diseases, brain cell death or nerve cell death commonly occurs. As a result, irreversible higher nervous functional disorders are developed. Once such functional disorders occur, the improvement, therapy and treatment of the diseases are very difficult and the QOL (quality of life) of patients is damaged for a long term. Consequently, although excellent preparations for oral administration which could prevent damage to these nerve cells are highly desirable for use prior to brain cell death or nerve cell death, such medicinal or pharmaceutical compositions have not been invented up to the present time.
Among the various ginsengs, red ginseng powder is frequently used in Chinese medical prescriptions, and it is positioned as one of the galenicals having various drug effects such as circulation improvement action and activation of the autonomic nervous system—endocrine system. It has also been reported that oral administration of red ginseng powder to patients with cerebrovascular disorder at chronic stage leads to improvement in cold flush or numbness in the lesioned extremities, as well as increased deep skin temperature. The effect is thought to be caused by the circulation-improving action of red ginseng powder (Yamaguchi, Takenori, Effect of medicinal ginseng on sequela of cerebrovascular disorder, in Ginseng '95, pp. 6-18, Kumagaya, Akira Ed., Kyoritsu Publishing Co.). However, if the red ginseng powder is administered orally to patients with cerebrovascular disorder at chronic stage (e.g. cerebral apoplexy patients at chronic stage), no improvement in cerebral apoplectic lesion itself is found. Further, it is not known whether the red ginseng powder is used for the prevention, therapy and/or treatment of cerebrovascular disorders at acute stage (e.g. acute cerebral apoplexy) in common clinical practice. Further, there is no known experimental medical basis for the use of red ginseng powder to treat other neurodegenerative diseases accompanied by nerve cell death, head injury or spinal cord injury in clinical medicine.
One of the inventors of the present invention (Sakanaka) has proved that when red ginseng powder at a dose of 0.9 g/kg/day or 1.5 g/kg/day, was administered to gerbils orally once a day for 7 days prior to a 5-minute transient forebrain ischemia, the learning disability after ischemia was significantly improved. This treatment also significantly prevented nerve cell death in the hippocampal CA1 area (Wen et al., Acta Neuropathol. 91, 15-22, 1996). Gerbils with forebrain ischemia are thought to be an animal model for transient ischemic attack in human. However, when red ginseng powder was administered orally at the same dose for one week after the 5-minute forebrain ischemia, the nerve cell death in the hippocampal CA1 area of gerbils was not suppressed; and the neuroprotective effect of oral administration of red ginseng powder was not so strong. Consequently, application of red ginseng powder to patients with more severe brain infarction than transient ischemic attack, e.g. to patients with permanent cerebrovascular occlusion), was thought to be unreasonable. Furthermore, the mechanism by which the oral administration of red ginseng powder suppresses the delayed neuronal death in the hippocampal CA1 area has not been elucidated. If such a mechanism of action is elucidated, it will be expected that new effects and improved efficacy of red ginseng powder will be discovered.
Originally, the methods for treatment of cerebral apoplexy (cerebral vascular diseases) have been different among cerebral infarction, cerebral embolism, cerebral hemorrhage, transient brain ischemic attack and subarachnoid hemorrhage; and strictly speaking, no effective countermeasures can be taken unless a cerebral CT inspection is performed. For example, thrombolytic agents can be used only for the treatment of cerebral infarction and brain embolism, and they are regarded as a contraindication for the treatment of cerebral hemorrhages. However, cerebral apoplexy is a serious disease resulting in a permanent disorder in higher functional activities, and threatening the survival of patients if no treatment is performed to protect the nerve cells or neurons at the lesion site at the earliest possible opportunity. Consequently, treatment or therapy should be initiated without a moment's delay. Even the period of time required for the CT inspection of the brain is, to put it strongly, a factor in reducing the possibility of recovery for patients with cerebral apoplexy. Surely, the treatment or therapy of acute phase cerebral apoplexy is a struggle against, not only the cerebral apoplectic lesion, but also the time after its onset. Quite unfortunately, at present, whatever is the disease type of cerebral apoplexy (cerebral infarction, cerebral hemorrhage, cerebral embolism, subarachnoidal hemorrhage or transient ischemic attack), the actual situation is that very few drugs are known which show a potent effect, even if they are administered immediately after the onset of cerebral apoplexy.
Ginsenoside Rb1 is a compound having the following chemical structure:
Ginsenoside Rb1 is a known compound described in the reference by Shibata et al. (Shibata et al., Economic and medicinal plant research, World Scientific, Philadelphia, pp. 217-284, 1985).
Intraperitoneal administration of ginsenoside Rb1 has been reported to show a tranquilizing action on the brain (Yoshimura H. et al., Eur. J. Pharmacol., 146, 291-197, 1988), but no mechanism of action has been elucidated. The possibility has been raised that a mixture of ginsenoside Rb1 and ginsenoside Rg1, or ginsenoside Rb1 or ginsenoside Rg1 at extracellular concentrations from 10−6M to 10−7 M is active in the central nervous system and shows some effect against Alzheimer's disease. This effect is the result of activating the liberation of acetylcholine from acetylcholine-containing nerve cells (U.S. Pat. No. 5,137,878: Composition and method for treatment of senile dementia). However, since it can not be said that the main cause of Alzheimer's disease is a functional disturbance of the acetylcholine-containing nerve cells, this hypothesis has many remaining problems to be solved. Further, the above US patent did not disclose problems whether ginsenoside Rb1 could extend the survival of acetylcholine-containing nerve cells, particularly whether it prevents the death of acetylcholine-containing cells or not.
In addition, the nerve cell-protective or neuroprotective action resulting from a single use of ginsenoside Rb1 has been hardly elucidated until we initiated the studies on ginsenoside Rb1. Using the transient forebrain ischemia model in gerbils, we have previously studied how the protective action of ginsenoside Rb1 is exerted for cells other than acetylcholine-containing nerve cells. It has been proved that in this forebrain ischemia animal model, occlusion of the bilateral common carotid arteries for 3 to 5 minutes while maintaining the brain temperature at 37° C. results in neuronal loss of hippocampal CA1 pyramidal cells (containing no acetylcholine). This occurs within one week after ischemia, depending on the occlusion time (this event is called delayed neuronal death). It is also noted that the learning behavioral function of the ischemic animals deteriorates (Wen T.-C. et al., Acta Neuropathol., 91, 15-22, 1996). These facts mean that the transient forebrain ischemia model of gerbils reflects the human pathologic condition which results from a transient ischemic attack (TIA).
One of the inventors of the present invention (Sakanaka) has proved that administering ginsenoside Rb1 (10 mg/kg or 20 mg/kg) into the peritoneal cavity of gerbils, once a day for one week in advance, can significantly prevent delayed neuronal death and the learning disability resulting from occlusion of the common carotid arteries for 5 minutes (Wen T.-C. et al., Acta Neuropathol., 91, 15-22, 1996). However, intraperitoneal administration of ginsenoside Rb1 immediately after a 3- or 5-minute occlusion of the common carotid arteries, produced no effect (Wen T.-C. et al., Acta Neuropathol., 91, 15-22, 1996; Lim J.-H. et al., Neurosci. Res., 28, 191-200, 1997). Consequently, since both the transition rate and the transportation rate of peripherally (intraperitoneally) administered ginsenoside Rb1 to the brain are thought to be very low, no clinical application of ginsenoside Rb1 was considered at that time.
One of the inventors of the present invention (Sakanaka) reported that intracerebroventricular infusion of ginsenoside Rb1 starting immediately after occlusion of the common carotid arteries for 3 or 3.5 minutes in stead of the above peripheral (intraperitoneal) administration suppressed the delayed neuronal death and learning disability (Lim J.-H. et al., Neurosci. Res., 28, 191-200, 1997). Further, the inventors of the present invention (Sakanaka, Tanaka and Maeda) proved that in spontaneous hypertensive stroke-prone (SH-SP) rats, with permanent occlusion of the cortical branch of the middle cerebral artery (MCA) (the cerebral infarction model of rats), intracerebroventricular infusion of ginsenoside Rb1 immediately after permanent occlusion of the MCA caused a significant reduction in the infarcted area in the cerebral cortex and ameliorated the ischemia-induced place navigation disability of the animals (Zhang B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998).
Even though ginsenoside Rb1 is effective in direct intracerebroventricular infusion, it appears impossible, however, to apply ginsenoside Rb1 to human transient cerebral ischemic attack (TIA) and cerebral infarction due to problems in the route of administration. These are similar to problems with other peptide growth factors (Sakanaka, M. et al. Proc. Natl. Acad. Sci. USA, 95, 4635-4640, 1998; Wen T.-C. et al. J. Exp. Med., 188, 635-649, 1998).
In order to identify compounds useful for treating, preventing or curing cerebral infarction, the methods for screening candidate substances for preventing, treating or curing cerebral infarction with the use of the cerebral ischemia/reperfusion model in gerbils or rats, have recently been frequently employed. However, it is important to note that the cerebral ischemia/reperfusion model using gerbils or rats does not always reflect, as explained later, the pathologic condition involved in human cerebral infarction. As described earlier, one of the inventors of the present invention (Sakanaka) has reported that in the cerebral ischemia/reperfusion model using gerbils, intraperitoneal administration of ginsenoside Rb1 at a dose of 10 mg/kg/day or 20 mg/kg/day, before cerebral ischemia, rescued approximately 30% of the nerve cells in the hippocampal CA1 area. (Wen T.-C. et al., Acta Neuropathol., 91, 15-22, 1996). Zhang, Y. G and Liu, T. P. reported that a single intravenous administration of ginsenoside Rb1 at doses of 10-40 mg/kg before ischemia, (using the ischemia/reperfusion model of the middle cerebral arteries of rats) reduced the infarction size approximately 20%-49% as compared with the control groups. Such an administration also reduced the infarction size approximately 12%-35% as compared with the control group when it was conducted after the reperfusion (Zhang, Y. G. and Liu, T. P., Chung Kuo Yao Li Hsuech Pao, Chinese Pharmacol. J., 17, 44-48, 1996). However, this effect can not always be said to be superior to the candidate substances of drugs (for example, glutamate antagonists and free radical scavengers) so far developed for treatment of cerebral ischemia/reperfusion, rather it may be inferior (Slusher, B. S. et al., Nature Med., 5, 1396-1402, 1999). Furthermore, the intravenous administration of ginsenoside Rb1 at the dose of 40 mg/kg, which produced a comparatively good effect and high efficacy for the prevention and treatment of cerebral ischemia/reperfusion injuries, as reported earlier by Zhang, Y. G. and Liu, T. P., can be said to be too high in dose. Consequently, we can not deny the possibility of side effects or ill effects appearing following the single intravenous administration of ginsenoside Rb1. This is true when we consider that the LD50 of the intravenously administered ginsenoside Rb1 is approximately 448 mg/kg (Saito, H., et al., Shoyakugaku Zasshi, J. Galenicals, 34, 177-181, 1980). For a single intravenous administration, such a high dose of ginsenoside Rb1 is critical, and intravenous administration on consecutive days (or continuous intravenous administration) may be difficult.
In case of actual human cerebral infarction (cerebral thrombosis or cerebral embolism), except for a few cases in which the thrombolytic therapy is performed after catheterization in the area of the obstructed cerebral artery for recanalization, there are many cases of permanent cerebrovascular occlusion. Consequently, a truly useful remedy for cerebral infarction is that it can be administered after permanent occlusion of a part of the cerebral arteries (for example, the middle cerebral artery), and the drugs which can protect specifically cerebral cells and nerve cells located in the ischemic penumbra until one month after the onset of cerebral infarction are needed. At this point, the cerebral infarct (cerebral thrombosis and cerebral embolism) lesion has entered a stable stage, and hopefully the broken cerebral vascular networks are recovered and reconstructed. It should be noted that the pharmacological analysis of drug candidates for the treatment or therapy of cerebral infarction should be performed by using animals with completely obstructed cerebral arteries. According to the earlier report by Zhang, Y. G and Liu, T. P., intravenous administration of ginsenoside Rb1 at a dose of 10 mg/kg to rats before permanent occlusion of the middle cerebral artery, resulted in absolutely no effect. However, only when ginsenoside Rb1 at a dose of 40 mg/kg was administered intravenously before but not after permanent occlusion of the middle cerebral artery, the size of the infarction was reduced about 14% as compared with the control group. Consequently, even if a single intravenous administration of ginsenoside Rb1 at the high dose (40 mg/kg) was performed earlier in rats with a permanently occluded middle cerebral artery, it produced an obviously weak effect as compared with results obtained from an intravenous administration of ginsenoside Rb1 into rats with ischemia and reperfusion of the middle cerebral artery. Furthermore, when the high dose (40 mg/kg) of ginsenoside Rb1 is administered to rats with permanent occlusion of the middle cerebral artery before cerebral infarction occurs, it produces a very weak effect. If we consider that the LD50 of ginsenoside Rb1 for intravenous administration is approximately 448 mg/kg, then such a high dose (40 mg/kg) of ginsenoside Rb1 for intravenous administration every day (or consecutive days) is thought to be impossible. Based on the experience of the inventors of the present invention, a single or one more intravenous administration of a drug candidate for the treatment or therapy of cerebral infarction into experimental animals with a permanently occluded part of the cerebral arteries (for example middle cerebral artery) may show an effect for 1-2 days after the onset of cerebral infarction. However, if the same drug candidate is not administered on consecutive days thereafter, the cerebral infarct lesion will surely expand, and eventually in one month after the permanent cerebrovascular occlusion (namely, when the cerebral infarct lesion enters the almost stable stage), almost no effect is observed. Consequently, an important qualification for drugs for the treatment or therapy of cerebral infarction is that the compound can be administered intravenously for a long term or intravenously every day. However, based on the previous report of Zhang, Y. G. and Liu, T. P., it was thought to be practically impossible to apply intravenous administration of the high doses of ginsenoside Rb1 in a repeated or continuous manner for treating, preventing or curing cerebral infarction or cerebral apoplexy.
The invention to counteract the previous idea that it was almost impossible to utilize ginsenoside Rb1 for the therapy, prevention or treatment of cerebral infarction, was developed by the inventors of the present invention (Sakanaka and Tanaka). Details are described in the specification of Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550 (Brain cell- or nerve cell-protective agents comprising ginsenoside Rb1) and Japanese Patent Application No. Hei 11-340850, PCT/JP99/06804 (Cerebrovascular regeneration/reconstruction promoters and nerve tissue secondary degeneration inhibitors comprising ginsenoside Rb1). In particular, we have found in the prior patent application that when repetitive or continuous intravenous infusion of ginsenoside Rb1 was conducted at a dose of 60 μg/day or 6 μg/day for 28 days after the middle cerebral artery (MCA) of spontaneous hypertensive stroke-prone (SH-SP) rats was permanently occluded, the volume of the cerebral infarct (cerebral embolism) lesion was reduced to about ¼ as compared to what occurred in a group of cerebral infarction infused with physiological saline (vehicle). That is to say, repetitive or continuous intravenous administration of low doses of ginsenoside Rb1, after permanent occlusion of the MCA, resulted in about a 75% reduction of the volume of the cerebral infarct lesions as compared with those in the control group. Moreover, it was found that even with repetitive or continuous intravenous infusions of such small amounts of ginsenoside Rb1 for 28 days, cerebral vessels which had been destroyed after MCA permanent occlusion were regenerated and reconstructed. This occurred even if the intravenous administration of ginsenoside Rb1 was subsequently terminated, and thereafter the cerebral infarct lesion had no longer deteriorated. Since the body weight of the SH-SP rats used by us (Sakanaka and Tanaka) is about 300 g, the daily dose of ginsenoside Rb1 is about 200 μg/kg or 20 μg/kg. Consequently, when this is compared with the single intravenous administration of ginsenoside Rb1 at a dose of 40 mg/kg that was used in the report by Zhang, Y. G. and Liu, T. P. (Chung Kuo Yao Li Hsuech Pao, Chinese Pharmacol. J., 17, 44-48, 1996), the daily dose to our SH-SP rats is 1/200 or 1/2000 of theirs. In the Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550 and Japanese Patent Application No. Hei 11-340850, PCT/JP99/06804, the inventors of the present invention (Sakanaka and Tanaka) invented an excellent method for treating or curing cerebral infarction (cerebral thrombosis or cerebral embolisms), and for the treatment or therapy of cerebral apoplexy and cerebrovascular disorders. This method involved the long-term intravenous repetitive or continuous administration of small amounts of ginsenoside Rb1. Small amounts of ginsenoside Rb1 can be administered as a single intravenous infusion every day, or as a small amount of ginsenoside Rb1 mixed with the other compositions or components for drip infusion so that the intravenous infusion can be performed constantly throughout the day or throughout a certain period. Further the prior report by the inventors of the present invention showed that the intracranial administration or the intracerebroventricular administration of ginsenoside Rb1 suppressed secondary degeneration of the ischemic nervous tissues (Wen T.-C. et al., Acta Neuropathol., 91, 15-22, 1996; Zhang, B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998). Also in the prior patent applications, the inventors of the present invention (Sakanaka and Tanaka) demonstrated that repetitive or continuous intravenous administration of small amounts of ginsenoside Rb1 suppressed effectively the secondary degeneration of the nervous tissues. And finally, in the prior patent application, the present inventors (Sakanaka and Tanaka) showed that repetitive or continuous intravenous administration of small amounts of ginsenoside Rb1 can be applied for prevention, therapy or treatment of neurotrauma, head injury or spinal cord injury.
In the pathologic states of cerebral apoplexy, neurotrauma, head injury, spinal cord injury, intracranial hemorrhage, cardiac arrest, hypoxic ischemic encephalopathy or encephalitis, etc., if a large invasion or damage into the brain and nervous tissues occurs, brain edema appears. As a result, the pressure on the brain is significantly increased and this frequently threatens the survival of patients. In the field of clinical medicine, in order to prevent, treat or cure herniation of the brain tissue which accompanies increases in brain edema or brain pressure (intracranial pressure), mannitol, glycerol and/or steroids are frequently used. However, problems from the rebound effect and other side effects following termination of the drug administration have not been solved. Consequently, a safe drug for the therapy or treatment of brain edema, which can be administered over a long time, may certainly be required in the future, but no such drugs are available.
Regarding a mechanism of neuroprotection by peripheral (intraperitoneal) administration of ginsenoside Rb1, the inventors of the present invention have reported that when low concentrations (0.1-100 fg/ml) of ginsenoside Rb1 were added in advance to the culture medium, the necrosis of nerve cells caused by the hydroxyl radical inducer (ferrous sulfate) was reduced (Lim, J.-H. et al., Neurosci. Res., 28, 191-200, 1997; Zhang, B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998). We presumed that ginsenoside Rb1 eliminated the hydroxyl radicals and thus reduced the lipid peroxide of the cell membrane and thereby protected the cultured nerve cells. However, no report to prove this hypothesis has been published.
High concentrations (approximately 0.11-11 μg/ml) of ginsenoside Rb1 reduced the neurotoxicity of glutamic acid and prevented nerve cell death (Kim, Y.-C., et al., J. Neurosci. Res., 53, 426-432, 1998; Liu, M. and Zhang, J. T., Acta Pharmaceutica Sinica, 30, 674-678, 1995). Also, the high concentration of ginsenoside Rb1 at 500 μM (550 μg/ml) may protect against apoptosis-like death in cell culture experiments (Tanaka, Tomoaki et al., The Ginseng Review, 24, 61-65, 1998). However, according to cell culture experiments by the present inventors, the high concentration of ginsenoside Rb1 did not suppress nerve cell death (Lim, J.-H. et al., Neurosci. Res., 28, 191-200, 1997; Zhang B., et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998).
It is very difficult to reproduce or maintain such high concentrations of ginsenoside Rb1 in the in vivo lesioned tissues or in the extracellular fluid of the nervous tissues. Furthermore, considering the cost and the possibility of side (ill) effects appearing, the present inventors (Sakanaka and Tanaka) speculate that the administration of large amounts of ginsenoside Rb1 in vivo is not feasible. Actually, in view of the earlier experimental results of the present inventors, it has been demonstrated that high doses of ginsenoside Rb1 do not always produce preferable effects and efficacy (Zhang, B., et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998).
At present, the mechanism of neuroprotection by ginsenoside Rb1 has not been elucidated.
In Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550 (Brain cell or nerve cell-protective agents comprising ginsenoside Rb1), we (Sakanaka and Tanaka) have found that ginsenoside Rb1, at a markedly low concentration range never previously reported suppresses apoptosis-like nerve cell death by increasing the expression of a cell death-suppressing gene product Bcl-xL. These concentrations ranged from 1 ng/ml or less, and preferably from 1 fg to 100 fg/ml. Specifically, in the previous patent application, we (Sakanaka and Tanaka) found that ginsenoside Rb1 is the only non-peptidic Bcl-xL expression stimulator in the world. Although ginsenoside Rb1 at a concentration of 100 fg/ml showed a slight suppressive action on the formation of lipid peroxides, no such effect was observed at the lower concentrations. Consequently, the hypothesis presented earlier in relation to the action mechanism of ginsenoside Rb1, namely the hypothesis in which ginsenoside Rb1 decreases cell membrane lipid peroxides as a result of erasing hydroxyl radicals to protect nerve cells, was found to be inappropriate. Further, in the previous patent application, the present inventors (Sakanaka and Tanaka) found that ginsenoside Rb1 inhibited apoptosis-like cell death in vivo.
Since Bcl-xL is expressed not only in nerve cells or neurons, but also in cells of the other peripheral tissues or glial cells, the fact that ginsenoside Rb1 enhances the expression of the cell death-suppressing gene product Bcl-xL, suggests that ginsenoside Rb1 also has the same action on the other cells. Importantly, we (Sakanaka and Tanaka) have described in the prior patent applications (Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550, Brain cell or nerve cell-protective agents comprising ginsenoside Rb1; Japanese Patent Application No. Hei 11-340850, PCT/JP99/06804, Cerebrovascular regeneration/reconstruction promoters and nerve tissue secondary degeneration inhibitors comprising ginsenoside Rb1) the idea that since myocardial cells abundantly express Bcl-xL, they are highly possible targets on which ginsenoside Rb1 at low concentrations and low doses act to show effect and efficacy.
Although ginsenoside Rb1 is a kind of purified saponin which is contained in medicinal ginseng, it can not be detected in the blood following a single oral administration. As a result, the pharmacological action resulting from oral administration of ginsenoside Rb1 has been denied. Consequently, in the Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550, Brain cell or nerve cell-protective agents comprising ginsenoside Rb1 and Japanese Patent Application No. Hei 11-340850, PCT/JP99/06804, Cerebrovascular regeneration/reconstruction promoters and nerve tissue secondary degeneration inhibitors comprising ginsenoside Rb1, we (Sakanaka and Tanaka) have demonstrated that intravenously administered ginsenoside Rb1 at low doses have effects, efficacy and/or usages independent of those of medicinal ginseng.
In the crude saponin fraction(s) of medicinal ginseng, besides ginsenoside Rb1, there are at least approximately 30 different purified saponins similar in chemical structure to ginsenoside Rb1 (Shoji, Ginseng '95, pp. 251-161, Kumagai, Akira, Ed. Kyoritsu Publ. Co.). Quite naturally, as described in our prior patent application (Japanese Patent Application No. Hei 10-365560, PCT/JP99/02550, Brain cell or nerve cell-protective agents comprising ginsenoside Rb1), these other purified saponins are expected to exhibit effects and efficacy similar to those obtained by intravenous administration of ginsenoside Rb1 at low doses. We have also described in our prior patent application (Japanese Patent Application No. Hei 11-243378) the concept that novel useful compounds could be prepared by using components of medicinal ginseng and/or ginsenoside Rb1 as the leading compounds.
As described above, we have referred to the importance of elucidating the mechanisms of action involved in oral administration of medicinal ginseng. We have also described the marked effects resulting from the continuous intravenous administration of small amounts of ginsenoside Rb1, the importance of prevention, therapy and treatment of cerebral edema, the upregulation of bcl-xL expression by ginsenoside Rb1, and the importance of elucidating the physiological actions of the crude saponin fractions of medicinal ginseng or components thereof. In the present invention, we have found that oral administration of red ginseng powder exhibited an unexpectedly excellent suppressive action against cerebral infarction, an ameliorating effect on cerebral edema and an improvement in place navigation disability in rats which had undergone permanent occlusion of the cortical branch of the middle cerebral artery (MCA). This damage caused by permanent MCA occlusion is more severe than the transient forebrain ischemia model of gerbils and is similar to the pathological state of human cerebral infarction. We have also found that oral administration of red ginseng powder enhanced the expression of the cell death-suppressing gene product Bcl-xL protein in the nervous tissues. Further, we have found that: the continuous intravenous administration of small or low dosages of ginsenoside Rb1 suppresses the onset of cerebral edema quite effectively; that ginsenoside Rb1 at concentrations of 0.01-104 fg/ml or 1-104 fg/ml enhanced the expression of Bcl-xL in myocardial cells and suppressed apoptosis or apoptosis-like cell death of myocardial cells; and that the continuous intravenous administration of small amounts of a crude saponin fraction of ginseng (red ginseng powder) exhibits therapeutic effects on spinal cord injuries. These effects were similar to those obtained by intravenous continuous administration of low dosages of ginsenoside Rb1. With these findings we have completed the present invention. In addition, we have found a novel chemical derivative of ginsenoside Rb1, i.e. dihydroginsenoside Rb1 which exhibits excellent therapeutic effects against cerebral infarction, and thus we have completed the present invention.